Endotoxins (LPS) of gram-negative bacteria fix to receptors on human red cells, granulocytes, lymphocytes, and platelets. We have shown that endotoxin receptors exist on the surface and inside white cells and platelets. These receptor-substances function as inhibitors which prevent attachment of LPS to human tissues and its components. The highly active substances are associated only with the lipid fraction of white cells and platelets. In this lipid we have detected 2 unidentified, possibly novel, bound fatty acids. We have also ascertained that the glycerophosphatides of the lipid fractions possess the highest activity. These phosphatides we intend to fully characterize. We will include in our studies separated B and T lymphocytes, and vascular endothelium, and murine spleen cells. We will quantitate endotoxin fixation to white blood cells with P32-E. coli O86 LPS and determine if it is reversible. The maximum number of LPS molecules taken up by white and red blood cells will be tested as well as the completeness of uptake of total LPS added. We will define the active groups on the inhibitors by partial degradation, blocking and substitution experiments. We have also preliminarily defined the structure of bacterial LPS which is complementary to receptors on human tissues. It appears to be amide-linked Beta-D-hydroxymyristic acid. We will extend these studies to selectively de-N-acylated lipid A and to de-O and de-N-acylated lipid A with intact pyrophosphate bonds in order to completely define the mode of attachment of endotoxin to target tissues. We will inject receptors and model substances along with endotoxin into animals to determine if they prevent, ameliorate or possibly reverse its toxic effects.